The compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, commonly known as Selexipag, is described in U.S. Pat. No. 7,205,302 B2. Selexipag is a prostacyclin PGI2 receptor agonist, marketed in the United States as UPTRAVI®, and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to delay disease progression and reduce the risk of hospitalization for PAH.

Crystalline forms of Selexipag are known, and have been disclosed, for example, in U.S. Pat. No. 8,791,122 B2, which reports non-solvated Selexipag Forms I, II and III, and WO 2017/040872 A1, which reports Forms IV and V. WO 2017/121806 A1 discloses equimolar solvates of Selexipag with aromatic hydrocarbons including o-xylene, chlorobenzene and toluene, which are reported to be useful in the provision of amorphous solid dispersions of Selexipag with a pharmaceutically acceptable excipient.
According to publicly available regulatory approval documents for Selexipag, such as the Australian Public Assessment Report (AusPAR), the drug substance Selexipag in the approved drug product UPTRAVI®, is Form I. This form of the drug substance is reported to exhibit pH dependent solubility and to fall within Class II of the Biopharmaceutics Classification System (BCS). Class II drug substances have high permeability but low solubility, which can present a challenge to achieving good bioavailability. Approaches to improving solubility and bioavailability of a particular crystalline form of a Class II drug substance include, for example, particle size reduction techniques, dispersion of the drug substance onto an inert carrier, and formulation together with solubilizing excipients. According to AusPAR, the drug substance Selexipag in the approved drug product UPTRAVI®, is subjected to micronisation to facilitate dissolution in the drug product.
A further consideration in the provision of a formulated Selexipag drug product is associated with the high potency of the drug substance given that the dose of Selexipag in the marketed UPTRAVI® tablets ranges from 200 μg to 1.6 mg. There are many challenges in manufacturing high potency drug substances that are related to, for example, safe handling practices to avoid inadvertent exposures, achieving content uniformity or homogeneity within the formulated product, accurate determination of the drug content in unit doses and effectively demonstrating cleanliness of equipment at very low detection levels.
Because Selexipag possesses the challenging characteristics of both low solubility and high potency, both particle size distribution (PSD) and polymorphism are two critical quality attributes (CQAs) that need to be strictly monitored and controlled in order to ensure consistent drug product performance (i.e., dissolution rate, bioavailability, solubility, stability, appearance, absorption and uniformity of content in low-dose tablets) and manufacturability of a solid dosage form (i.e., granulation, milling, flow properties of the blend for compression and encapsulation).
Different crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Differences in stability between solid forms of a drug may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, including a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Particular crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in solubility between crystalline forms are particularly relevant for drug substances exhibiting low aqueous solubility, such that even a modest increase in solubility may provide a beneficial enhancement in bioavailability.
Additionally, the particle size of a given crystalline form upon isolation from a suitable crystallisation system may be finer than a different crystalline form, corresponding with increased surface area and the potential for enhanced solubility. Particle size can be particularly critical for high potency substances, and smaller particles are generally preferred during the formulation of high potency drug substances to ensure content uniformity in the dosage form. Different physical properties of crystalline forms may also affect their processing. For example, the particle morphology or crystal habit of a particular crystalline form may result in differences in bulk properties such as flow rates and density, resulting in more resistance to flow, or inefficiency during filtration and/or washing. Furthermore, particle morphology can have an impact on micronisation practices that are typically used to further reduce the particle size of high potency drugs, with some morphologies being more resistant to breakage and processing than others.
Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains even more elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).
Particularly due to the low solubility and high potency characteristics of Selexipag, both of which lead to considerations related to crystalline form, there exists a need for novel crystalline forms of Selexipag for use in providing improved drug products containing Selexipag and their manufacture.